EFFECT OF SUBSTITUTION SITE UPON THE OXIDATION POTENTIALS OF ALKYLANILINES, THE MUTAGENICITIES OF N-HYDROXYALKYLANILINES, AND THE CONFORMATIONS OF AKYLANILINE-DNA ADDUCTS

Carcinogenic arylamines typically undergo metabolic activation via N-h ydroxylation followed in most instances by O-esterification. In this s tudy, the ability of methyl-, dimethyl-, and ethylaniline constituents of tobacco smoke to undergo oxidation at the nitrogen atom was analyz ed. In addition, the mutagenicity of the corresponding N-hydroxyalkyla nilines and the conformational properties of the DNA adducts generated from their N-acyloxy derivatives were investigated. All the arylamine s underwent irreversible electrochemical N-oxidation at potentials hig her than those observed for the oxidation of carcinogenic polynuclear aromatic amines. There were minor differences in the oxidation potenti als, which were consistent with the position and electron-donating abi lities of the alkyl substituents; however, the differences appeared to be too small to account for the range of genotoxic effects among the alkylanilines. N-Hydroxyarylamines containing p-alkyl substituents had increased mutagenicities in Salmonella typhimurium TA100, which was a ttributed to their higher efficiencies of adduct formation. Increased mutagenicities were also observed upon o-alkyl substitution; however, this property was not related to a greater ability of the ortho-substi tuted species to form DNA adducts, which suggested that adducts from o rtho-substituted alkylanilines may be intrinsically more mutagenic tha n their meta- and para-substituted analogues. In all instances, N-(acy loxy)arylamines generated from the N-hydroxyarylamines reacted with dG , dG nucleotides, and DNA to yield C8-substituted dG derivatives as th e major adducts. The alkylaniline-dG adducts displayed distinct confor mational trends that were determined by the location of the alkyl subs tituents. Spectroscopic data indicated higher percentages of low-energ y syn conformers in the adducts that contained alkyl groups ortho to t he arylamine nitrogen as opposed to adducts not bearing ortho substitu ents. The data strongly suggest that the conformational properties of the DNA adducts, in particular their ability to adopt syn conformation s, may be determinant factors for the genotoxic responses elicited by certain alkylanilines (e.g., 2-methylaniline and 2,6-dimethylaniline).